Welcome to the Cowen Conference. Representing the company is Samit Hirawat, who is Executive Vice President and Chief Medical Officer and the Global Head of Drug Development. Thanks, Samit, for making the time to be with us. Lots to talk about. Lots going on in the Bristol pipeline. We'll jump right in. Let's start with SOTYKTU, which is off to a just a terrific start in the marketplace for psoriasis. You're working on a number of other indications. Those are in development. Can you kind of order them relative to your conviction and/or the market potential and just remind us where those additional indications for SOTYKTU stand today? Sure. Thanks, Steve, for the question, certainly very fortunate about the Bristol Myers Squibb pipeline and in terms of pioneering the way for the first in class TYK2 inhibitor. TYK2, first of all, great start thanks to our teams who've delivered on the promise of SOTYKTU and a TYK2 inhibitor in moderate to severe plaque psoriasis. We've showcased the data in the past on the phase II trial in psoriatic arthritis that paved the way for initiation of the phase III trials in psoriatic arthritis that are enrolling as we speak. We also have shown the data in the phase II setting in a randomized trial for systemic lupus erythematosus, the largest of its kind in the phase II study, with very promising data that encouraged us to engage with the health authorities to design the phase III program. We actually launched the phase III program in January of this year as well. We also had talked about the ulcerative colitis data a year and a half back where we did not have a proof of concept, so we need to retest the hypothesis. Those studies in Crohn's disease and ulcerative colitis are ongoing. Those are phase II studies, and as we have communicated before, we are looking forward to seeing the data in the first half and the second half of this year respectively for Crohn's disease and ulcerative colitis, and we'll provide an update on those. Beyond that, there are a couple of other programs that we are working on, you know, the lupus erythematosus phase II is already on clinicaltrials.gov. We are enrolling in that trial. There is one more indication that we will be able to talk about later this year once we have initiated that trial. Okay. you mentioned when starting to talk about SOTYKTU that it's first in class. Obviously, it is. There's a number of competitors coming, both within the TYK2 space but also kind of adjacent spaces. Maybe you can just tell us why SOTYKTU is not only first in class but will be best in class. We do believe Well, first of all, by default, if you're the only one, you are the best in class. Well, that's true, yeah. That's the beginning point. If you think about it now, the specificity of it, downstream effect, it's IL-12, IL-23, and interferon. These are the three cytokines we hit. Based on the science that evolved from there is why we pursued the individual indications. Interferon, SLE makes perfect sense. IL-23, IBD makes sense. That's why we are pursuing it. IL-12, IL-23, of course, made sense for psoriasis. We pursued that. Psoriatic arthritis, we pursue that. Similarly, eruptive psoriasis makes sense. If you think about the competition, there are two elements to it. One is in the oral space. One is the biologic space. In the oral space, certainly, there are other TYK2 inhibitors that are in development. Now, of course, I think competition is good. Innovation is good. Anything that can come and be better is certainly welcome because it is important that we keep the patient in the front and center. If something helps the patient more, we're all for it. However, whatever comes next, whatever the competition is, needs to be able to demonstrate that it is better than what is out there. We are no longer in the space of science and drug development where mediocrity should be accepted, where similarity or similar, you know, me too drugs are going to provide better outcomes for patients. We need to see what is better. It is for the next generation of molecules to now prove that they are better or differentiated, and we'll look forward to those data. Similarly for injectables, I think, are they going to be specific to IL-12 or IL-23 or interferon or promiscuous, as in multitude of targets that they're hitting? Dependent on that data, again, it will be good to see where they belong with, as it relates to SOTYKTU. I know that some data has been talked about this morning, from an IL-23 perspective. I just heard about it. I didn't see it. It'll be interesting to see when the data are released, what they really mean and what the impact is and where they fit in the overall treatment scape, landscape. Okay. maybe we can move to another, recently launched, asset for Bristol, and that's Zeposia. This is another product which, will at some point get competition in the GI space. Yeah. Talk about that dynamic and is this another one where you feel Zeposia still has an opportunity to be the leader? Remember, Zeposia as an S1P modulator, it's got two indications right now, multiple sclerosis and ulcerative colitis. The study in Crohn's disease is ongoing. We did have an impact. We talked about it because of COVID and then geopolitical situation that goes on. Certainly we are enrolling that study, and we are hopeful that we'll be able to get that completed soon. There will be competition, especially in the ulcerative colitis space as the next S1P modulator comes into the marketplace. We believe we do have differentiation still. If you think about the label, and we'll have to see what the label ultimately comes out for that competitor drug. If you think about the first dose monitoring, we don't have that. That's an important element of that. Having more than one indication certainly helps in terms of continuously establishing the profile, generating the data, and providing the safety updates, et cetera. So looking forward to what comes next and we'll continue to evolve from that perspective. From a commercial perspective, this is an important year for Zeposia as well, as we look towards the growth trajectory for Zeposia in that marketplace. By the way, I should have mentioned, should you have questions along the line, please just raise your hand and we'll call upon you. From the drug development standpoint, not the commercial standpoint, but from the drug development standpoint, how do you differentiate Zeposia and SOTYKTU in the GI space? I think it is all going to be data dependent. For SOTYKTU, as we spoke just a little bit earlier, we do not have that proof of concept to showcase the remissions or outcomes in terms of disease outcome, in terms of patients with ulcerative colitis and Crohn's disease. One of the hypotheses we want to test is higher dose going to be better in terms of causing and leading to the decrease in the symptomatology and increasing the clinical remission rate for ulcerative colitis. We are testing that hypothesis. On the flip side, for S1P, we convincingly demonstrated the impact and the clinical remission rates that we saw in ulcerative colitis. We have to repeat that experiment for Crohn's disease. In general, those diseases track quite well with each other. We have to still wait for the data to see if we can get that in the label when the data reads out. The GI space is bigger than IBD only. Remember, cendakimab is the third molecule that we have, which is in eosinophilic esophagitis, so upper GI. We do believe that it's a differentiated molecule. It's an IL-13 inhibitor. It inhibits both isoforms of IL-13. Now, of course, the question is what else is out there and how is it gonna differentiate itself? There is DUPIXENT, IL-4 inhibitor, which also indirectly inhibits IL-13, but only LPA1 isoform. R2 isoform is important from a remodeling and fibrosis perspective, in addition to the inflammation that occurs in this disease. The phase II data are very strong, and so we are right now enrolling the eosinophilic esophagitis trial phase III study. When it reads out, we are hopeful that this will be the second drug that might be available to patients with this disease. You pretty much already answered this question, but when you step back and look at EoE, what is the unmet need that DUPIXENT currently is not meeting? Is the mechanism of DUPIXENT not giving the full response that you would expect from cendakimab? Is that the answer? That is our hypothesis and our scientific rationale to pursue IL-13. There are two elements to it. One is the inflammation, and second is fibrosis, right? What we've seen thus far from the data perspective, certainly there is an impact on inflammation with DUPIXENT, and we've seen that. What we saw for cendakimab is in a small study, but phase II randomized trial, is also endoscopic evidence on improvement in that fibrosis, which should translate ideally into decrease in the dysphagia days. That is one of the elements that we have included in the study to be able to measure the decrease in the dysphagia days. If that is achievable, that is a big unmet medical need that we will be able to serve. Okay. Dysphagia obviously meaning lack of appetite, so days- Yeah, you can't eat, right? Okay. There is the esophagus that is constricted, so you can't swallow and get the data. Cendakimab, to the best of our knowledge, was also in development for atopic dermatitis and now is no longer. Why was that decision made? We certainly want to be very mindful not only of the landscape, but also how we differentiate ourselves as we get into the landscape. We talked about it earlier, that it makes sense to develop drugs which are differentiated, that are not necessarily going to be me too's or not going to be something that just is going to provide minuscule improvement on what are established therapies, available therapies. In atopic dermatitis, we set our bar in terms of, first of all, readout of the primary endpoint of the clinical trial. For development, we made sure that we set a bar ourselves to say we need to be better than what is out there. It's a very crowded field in atopic dermatitis. Lots of drugs have come through just recently. As we look at that data in that landscape that is out there, we didn't think that there is enough in that data set to showcase a differentiation and something that will stand out, and as your question was before, that will really meet the unmet medical need in that disease. It does not make sense for us to continue to invest in that indication, much rather we would focus on something else because our pipeline is quite full and healthy. Okay. Questions from the audience? Let's move on to Milvexian, perhaps the most important drug, I, that you might be developing. Maybe you can update us on where you stand in phase III. If you call Milvexian a very important drug in the overall pipeline in cardiovascular space, Factor XIa inhibitor, we have initiated first trial with Janssen in the secondary stroke prevention. That is a 15,000 patient study, 25 milligrams BID dose based on the data that we had collected in the phase II. The second and the third study, which we have declared publicly, will be starting within this half of the year, within the first half of the year in atrial fibrillation and second one in acute coronary syndrome. Acute coronary syndrome, that is in, with the background therapy of antiplatelet agents similar to SSP, whereas the third study in atrial fibrillation is the single agent versus apixaban. That's what we recently announced in a press release. Are there any meaningful differences, between the phase III studies and, meaning such as enrollment criteria, safety endpoints, patient subgroups, compared to the successful trials in phase II that you've already run? Not in a major way. We are still looking at the similar endpoints, not only from a safety efficacy as in prevention of ischemic strokes in the phase III trial. Not in a major way. We're trying to replicate and improve on the data that we have seen in the phase II. Safety is gonna be a very big component today because these patients are not treated with anticoagulants because there's a bleeding risk with antiplatelet agents being on board. That is going to be a very, very important element to this development. You announced these, three trials, one initiated, two to come. Paint for us the picture of what the ideal outcome is in each one. If you could add any numbers, that would be phenomenal. Yeah. Too early to add numbers. We haven't really declared the statistical analysis plan for these trials, but you can imagine these are thousands of patients. The first study is 15,000 patients, the other two we'll talk about once we have declared the overall design as to what the dose is and what the overall sample size is. The outcomes are pretty simple and straightforward as such. If you think about secondary stroke prevention, the outcome would be from an efficacy perspective, prevention of ischemic strokes, similar to what we have tried to show in the phase II study, and of course, the outcome from a combinability and safety perspective, not having fatal or serious bleeds as we combine to the background therapies. Same is the outcome for acute coronary syndrome, again, preventing, the events, cardiac events in that particular study. It same to, same as atrial fibrillation. We've seen that, with apixaban already in ELIQUIS trials, so replicating those endpoints. Here we have an active competitor, so certainly the bar is high, but we are hopeful and confident that we'll be able to achieve that as we launch that program. We are not getting into the specifics of the statistical design and the superiority margins that we've set for ourselves. Two of the three trials have an active comparison. Sometimes, you know, we witnessed situations where when drugs get to phase III, much larger population, much more heterogeneous, lots of centers, global, different standards of care, and all of those factors or some subset of them leads the trial to have a different outcome than we saw in phase II. Yeah. That must worry a drug developer such as yourself that things aren't gonna be perfect in phase III. How did you guard against that? I think experience does matter in these situations. Managing and what you've seen in the past that works and doesn't work becomes very important to replicate or dissuade from a team's perspective to not do. Here we have two companies joining up our minds as we look at designing these studies, as we did design these studies. We engaged the regulators on both sides of the pond to get an input into the trial designs, agreeing on the overall statistical plan and what the endpoint should be. As we look to the future, both teams are gonna be really heavily engaged in terms of data monitoring and cleaning up the data so that we can raise a flag if we start to see things deviating from the norm. We will have DMCs in all these trials, so Data Monitoring Committees who are gonna be paying attention to the evolving safety data as well. They will keep us honest in terms of making sure that if they see a signal, that we are aware of it, and then we manage it. Those are all the. You know, any drug developer would think about any of these things, and we just have to ensure that the teams pay a close attention to the enrolled patients, that they're not deviating from what is written in the protocol. This is another market where you have competition. How do you think Milvexian stacks up against the competitors? It's difficult for me to really do apples to apples comparison because they're two different companies, two different drugs, two different trials that were conducted. You've seen the data that the competitor Bayer has presented as well as we presented. We do believe that we have a big therapeutic window, although it's BID dosing, but we have the advantage of a shorter half-life in a way. We do believe that we have the experience from ELIQUIS days of BID dosing. Many people have asked us the question, "Is BID a disadvantage?" We don't believe twice-a-day dosing is a disadvantage at all. I think the overall experience of conducting these trials and being able to combine the brains of two companies does have its own advantages, I think. It's hard for me to say ultimately where the cards will land and how they will ultimately showcase, but we are very confident in the overall plan. I know that our sample size is larger. For SSP, we believe the statistical significance and clinical meaningfulness might require that sample size to be there. Okay. Let me ask one more question about Milvexian and then one on Camzyos, then I'll turn it to Mike for some additional questions. Remind me, did any ELIQUIS study stop early for either efficacy or safety? I know the vast majority of them worked out successfully. One, I think, did not, but did any of them stop early? I don't remember, but it did. ACS. Okay. Okay. On Camzyos, what is the development path from here? It's on the market off to a constructive start. What's the development path from here? Absolutely. Myosin inhibitor, cardiac myosin inhibitor, Camzyos. First approval obviously done with obstructive hypertrophic cardiomyopathy in the US. Then, of course, the second study has initiated now in non-obstructive hypertrophic cardiomyopathy as a phase III in January, we're looking forward to enrollment of that trial. We have a proof of concept study, EMBARK, that is ongoing in patients with HFpEF or heart failure with preserved ejection fraction. We'll look at that data later this year and see if that is meeting the muster to be able to then think about larger and longer plans. We'll keep you posted on that. Those are the three major indications. As we think about additional indications, we'll let you know. Those are the three major ones. Yeah. Let's turn to oncology and talk about Opdivo a little bit. Growth of Opdivo is dependent in large part now on success in adjuvant and neoadjuvant settings. Can you remind us where you stand with Opdivo in key tumor types in those settings? Sure. Obviously, lots of approvals already in our hands and certainly Katherine is here. Later on, if anybody wants questions on the market opportunities and how we are performing, Katherine will be able to answer those questions as well. With that said, though, from what I know and I understand from my commercial colleagues, overall, Opdivo is doing really well from the GI indications perspective as well as continuing to make progress in the lung cancer space because we have the neoadjuvant indication. Certainly making progress over there. Melanoma-wise, obviously, not only because of the combinations that we already have with ipilimumab in the past, but because of Opdualag even continuing to really do very, very well in that situation. Now, of course, as the next iteration to that, we are looking forward to the readout of the non-small cell lung cancer trials. 73 L is in the non-resectable stage three non-small cell lung cancer. That is still to read out. 77 T, which is our peri-adjuvant study, where we will have the new adjuvant and the adjuvant parts in the study. We're looking forward to those readouts. While they don't contribute in the next two years, beyond that might be very interesting and important as well. Your competitor recently posted positive peri-adjuvant lung cancer data. Exactly. Is there any difference in trial design that are notable? They're very similar, I would say. Plus, remember, we already have the new adjuvant covered. Yeah. Now what 77 T will add is the adjuvant portion to our already established new adjuvant position. Is there any hope left for a checkpoint inhibitor in prostate cancer? Look, we have our own study that is still to read out, 70 X, we'll wait to see what that data will tell us. I think we have to continue to hope, and we have to continue to learn from the science that we do. If it doesn't pan out, if it doesn't work out, we'll learn something more as to what the mechanisms of resistance might be over time as we look deeper into the biomarkers. We go back to the drawing board and say, which other drugs should we be developing that comes in here? Remember, from a prostate cancer perspective, our protein degradation platform has given us a new molecule that we are quite excited about, the androgen receptor ligand-independent degrader. We are developing that. That's in phase I. We are starting to see the data that's quite promising. We are hoping to have a proof of concept done by the end of this year, then next year, hoping to bring it into late-phase development as well. You mentioned Opdualag, which has been performing well in melanoma. phase II data in frontline lung cancer are coming this year. Can you help us help shape our expectations for that readout? What data are we actually gonna get. Sure. How important is it to your fancy? Overall, if you think about the Opdualag program, the first indication, yeah, we have that covered from a FDA approval perspective. We have finished enrollment in the adjuvant study of melanoma as well. Over the next couple of years, we'll see the readout as well. We have an ongoing phase III study in colorectal cancer MSS. That should finish enrollment this year, and next year we should be able to see the data. In non-small cell lung cancer, we have a randomized phase II study that is ongoing, looking at Opdualag plus chemotherapy versus nivolumab plus chemotherapy. It's a randomized phase II study. We are using that to, number one, answer the question of a contribution of components. What does LAG-3 add on top of a PD-1 plus chemotherapy? This will also give us a good understanding that if the data do pan out and show superiority to the doublet of PD-1 inhibitor plus chemotherapy, then we can go to phase III in a two-arm trial of Opdualag plus chemotherapy versus the established PD-1 inhibitor that is Keytruda plus chemotherapy. That's the intent, but we have to wait for the data to read out. How important is the adjuvant melanoma trial to Opdualag's future? I think it's a critical element in the overall Opdualag development, and I think LAG-3 has shown a great promise in the metastatic setting. It's quite natural to progress it further into the earlier setting to hopefully see an outcome that benefits even more patients because melanoma patients, yes, and over the 10 years we've made a lot of progress, but still an unmet medical need from a long-term outcome perspective. What other fixed-dose combinations are you exploring with Opdivo? Right now, we have lots of combinations ongoing, and depending on how the overall efficacy profile evolves from those combinations, we can think about combining with other agents. We have not declared anything yet from an FTC perspective or FDC perspective, as to what combinations we are pursuing as a fixed-dose combination. We have not declared that. Let me just interject. Is it likely that, you know, data dependent, that you will continue to pursue this strategy with [Hastor, was it one and done? Whenever possible, we will. Okay. You know, one of the potential combination partners is an anti-TIGIT. What is your thought on TIGIT as a target given the data we have to date? I think jury is out on TIGIT. It's not a proven mechanism yet that it doesn't work or it works. We saw some interesting data over time from several players in the field. phase IIs have panned out, but I think Steve's question early on, as you go to phase III, things don't necessarily work out the same way as they did in phase II. Now, why does it happen? Sometimes it's the heterogeneity of the tumor, sometimes it's because we try to do too much in the phase III because we wanted to go for a larger population. Sometimes we select different patient populations. Sometimes it's the dose, sometimes the schedule. And that data has not really been shared thus far from the studies that have completed, so we'll have to wait, watch out for them. One thing that is different for us, we looked at the mono-specific TIGIT first, in combination with nivolumab plus epi, and we saw that, number one, we were late, number two, we saw a safety signal. We said, "Okay, we'll stop that." We have the next TIGIT, which is a bispecific. We do believe that there are other pathways that open up once you're blocking TIGIT. While we have not declared what the second target is, it'll be interesting to see what that does as it shuts down the overall pathway and can that lead to better outcome. We have the single agent phase I ongoing. We've just initiated the combination as well with nivolumab, and that data when it reads out will tell us more about the TIGIT. TIGIT is an interesting target. We can't give up yet on that. When can we expect data from the bispecific? It'll be next year, not definitely not this year. Your comment on the phase II not translating to phase III is an interesting one. That was Steve's comment, not me. It's Steve's comment. I just added to that. Yeah, yeah. It was definitely notable in the TIGIT field. Back on the topic of Opdualag in the phase II lung cancer data we're gonna get, is that trial designed in such a way that we should have more or similar confidence relative to this potential issue of moving to phase III? Do you view this as an issue that's specific to IO or just a sort of clinical trial? No, it has happened many times that phase II doesn't translate to phase III or the phase II data all the way. Historically speaking, and if you think about it, what happens in the phase III, it dampens out in the phase III because of all the reasons that were already spoken about. From a Opdualag non-small cell lung cancer study, if the data does read out, we've set ourselves some bars that we need to achieve a certain threshold to progress to phase III, otherwise we don't. We have to really live up to that promise of the drug and product profile, that if we get the profile, then we proceed. Can you give us a sense what that bar might be? No, not yet. Fair. That's fine. Let's move on to IMiDs and cell therapy. How are you planning to position iberdomide and your other follow-on IMiDs relative to Abecma? Let's start with there is a complete differentiation in terms of what these therapies are. Abecma, cell therapy, truly transformational, highly efficacious, leading to complete remissions as well as PRs. Started in the late-line setting, fifth line plus. Now we have data in KarMMa-3 in the third line plus patient population. Looking forward to getting that to the patients soon. That population is a set population. Not everybody is going to be getting cell therapies. You need the right setup. It is still limited to the academic centers where patients can actually be treated, side effects are managed if they occur, et cetera. IMiDs are more. It's a small molecule, number one, first of all, and CELMoDs are small molecules. What we are thinking of iberdomide and mezigdomide is a combination strategy with standard of care therapies to begin with. That's why we are doing three phase III trials, one for iberdomide, looking at a combination with daratumumab and dexamethasone, comparing to Velcade, daratumumab, dexamethasone. Replacement of Velcade strategy, if you think about them. This is in the second line plus patient population, one to two prior lines of therapy achieved. For mezigdomide, which is a more potent molecule, that means it does have liability that it can't be combined with everything. We have to be choiceful. We are not combining with daratumumab. We wanted to ensure that we do compare versus pomalidomide. We have a study of pomalidomide Velcade dexamethasone versus mezigdomide Velcade dexamethasone. Here we are replacing pomalidomide. The third trial is also with mezigdomide, is a replacement or rather add-on strategy with Kyprolis and dexamethasone. Kyprolis dexamethasone versus mezigdomide Kyprolis dexamethasone. If I were to bundle it all together, if you think about CELMoDs, in the second line plus space, about 60% of the patients are treated with one of the three combinations: PVd, VDD or with Kd. Iberdomide and mezigdomide actually captures that patient population. The next iteration on that later this year, what we intend to do is initiate a trial for iberdomide in the post-transplant maintenance space, comparing it head-to-head versus REVLIMID. We believe that could have a better outcome for patients. Once that study starts, we can take a deeper look into that as well. Great. In the last minute, I'll turn it back to Steve to ask. Final question. You probably have a pretty good understanding of where investors think Bristol development will be, say, in 10 years. You have a lot greater knowledge of where Bristol development will be in 10 years. What do you think will be the biggest surprise that investors are not appreciating now? Is it the breadth of the pipeline? Is it the capability of certain assets? What is it that we, that we don't know that will surprise us? Tim will kill me when I say this, it's okay. I think... Again, look, I'm a drug developer, so I know a little about the dollar signs. What I do think is the least underappreciated, and this may not just apply to BMS, but everywhere else, is not much value is given to the early pipeline. If you think about our early pipeline, there are about 50 assets in development. We've publicly stated that we anticipate that over the next 18 to 24 months, we should have about 15 proof of concepts. We've spoken about already that apart from the nine newly launched products, we will have six in phase III development, new molecular entities by the end of this year. Beyond that, we've talked about CELMoD-282, we've talked about AR LDD as a protein homeostasis platform outcome. We've talked about GPRC5D as a third cell therapy in our pipeline. We've talked about alnuctamab. All of them will enter late phase development as well. I think that for me, that's a surprise that it doesn't get the value that it should get. Yeah. That could be something that will be a surprise at the end of the decade or early next decade, that these all turn into major impactful transformational products. That would be a pleasant surprise and a fascinating conversation, Samit. I appreciate your time. Thank you. We wish you well. Thank you so much.